While antigen specific-IgE is important for immunity against intestinal helminths, these pathogens generate high levels of largely non-specific IgE. This hinders the parasite-specific IgE thereby reducing mast cell degranulation and anti-helminth immunity. Thus, this represents a protective response that has evolved for the helminth: non-specific or low affinity IgE blocks high affinity IgE receptors (Fc?RI) and thereby protects the helminth. The initial studies in this proposal indicate that B1 cells are responsible for the large IgE induced by helminth infection, in which cytokines act on B1 cells, promoting IgE production. In this application I further examine B1 B cell IgE production as the source of non-specific IgE in helminth infection, and then investigate the protective capacity of B1 IgE as an explanation for why helminth infection is protective against allergic disease. To this end, I plan to utilize a mouse model with a membrane IgE reporter to track the development of IgE in B1 compartments during helminth infection as well as rounds of division needed to class switch to IgE. I will additionally use a Rag1-/- mice reconstitution model, in which B1 or B2 cell IgE contributions to helminth infection clearance can be examined. I also plan to investigate the role of the cytokine IL-5 as a priming agent for B1 cell IgE production. The class switch recombination patterns of IgE have never been examined in B1 cells. I plan to analyze the switch regions (s), s? to s? for s?1 fragments. This protocol will determine if B1 cells undergoa direct switch from ? to ?, which is typical for low-affinity antibody production. Next, I plan toshow the B1 IgE can block MC degranulation in models of anaphylaxis. Also B1 IgE production will be assessed utilizing the reconstituted RAG-/- mice that are helminth infected and then sensitized to house dust mite (HDM) in a MC-dependent HDM model of mouse asthma. The reduced airway hyper-responsiveness seen with concurrent helminth infection should be diminished in B2 only reconstituted mice without the presence of B1 IgE. Next, I will test the underlying factors that push B1 cells to IgE in helminth infection. Preliminary evidence indicates that IL-5 may prime B1 cells to switch to IgE, I will expand the B1 cells with IL-5 and compare the IgE production in RAG-/- mice reconstituted with the IL-5 expanded B1 versus B1 from nave mice. I hypothesize that IL-5 will push B1 cells to IgE production and when these mice are subjected to a HDM asthma model, they will have a decreased response as compared to non-IL-5 primed B1 reconstituted mice.